ProjectSummary/Abstract The Medicines for Malaria Venture (MMV) recently published a ?roadmap? for the types of medicines that are needed to support the long-term goal of malaria eradication. The roadmap consists of a wish list of target candidateprofiles(TCP)andmedicines(targetproductprofiles,i.e.,TPP).Withthemostrecentrevisiontothe anti-malarialtargetcandidatesandproductprofilestheMMVhighlightedtheneedforidentifyingnewmedicines for chemo-protection and chemo-prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2)(Burrows,JNetal.,2017,MalariaJournal,16:26).Accordingtotheirupdatedroadmapnewdrugsare needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver-stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil.TheMMVenvisionsthataninjectablesustained-releaseformulationcouldbedevelopedasalong- actingpreventativeprovidingupto3to4monthsofprotection. As a potent and selective inhibitor of the parasite?s cytochrome bc1 complex, ELQ-300 targets Plasmodium falciparuminthebloodandliverstagesandevenkillsparasitesdevelopinginthemidgutofthemosquitovector. WithsupportfromtheNIHandUSDODwehavebeensuccessfulindevelopinganoralformulationofprodrug ELQ-331 for use in humans for weekly prophylaxis against malaria, work that was performed in collaboration withSRIInternational.InthepresentapplicationweseekNIHsupportforacomprehensiveassessmentofELQ- 300 prodrugs for intramuscular injection to effect the sustained-release of drug from an oil depot (or other extendedreleasematrix)intothehostbloodstreamatlevelsabovetheminimumeffectiveconcentrationneeded to block liver stage infection by infectious sporozoites. In collaboration with SRI International we will leverage our knowledge of ELQ-300 prodrug chemistry, crystallinity, stability, and solvent/vehicle solubility with their expertise in formulation design and optimization to identify the optimal ELQ-300 prodrug design that is paired with an optimal depot formulation to provide long-term protection of animals from sporozoite infection. Four different prodrug chemistries will be evaluated and compared, varying R-group chain length to optimize the physiochemicalpropertiesofthedrugandtoenhancesolubilityinvehiclesandmixturesthatareapprovedfor humanuse.Theoverallgoalistodevelopalong-actingsustainedreleaseformulationofanELQ-300prodrug forchemo-protectionagainstmalaria.